JP2925382B2 - Method for producing 1α-hydroxyvitamin D2 derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

Relates to a manufacturing method of the present invention 1α- hydroxyvitamin D ₂ derivatives BACKGROUND OF THE, details the general formula (I)

[0002]

Embedded image

(Where A ¹ is a general formula (a)

[0004]

Embedded image

Wherein R ² and R ³ each represent a lower alkyl group or a trifluoromethyl group, or together with the carbon atom to which they are attached, represent a carbocyclic ring. , X ¹ and Y ¹ each represent a hydrogen atom, a fluorine atom, a methyl group, a hydroxyl group or a protected hydroxyl group, and n represents an integer of 1-4.
The present invention relates to a method for producing a hydroxyvitamin D ₂ derivative, and a novel intermediate compound useful in the production method.

[0006] 1α-hydroxyvitamin D ₂ derivatives represented by the general formula (I), such as 1α-hydroxyvitamin D ₂ , 1α, 25-dihydroxyvitamin D _2, are used for chronic renal failure, hypoparathyroidism, and bone softening. Is known to be effective in treating calcium metabolism deficiencies such as osteoporosis and osteoporosis. Also, (24R, 22E) -9,10-secoergosta-5,7,10 (19), 22-tetraene-1α, 3β, 25-triol is known to be effective in treating skin diseases such as psoriasis. ing. Also, 1α,
The 24-position epimer of 25-dihydroxyvitamin D ₂ is
It is a compound that has attracted attention because it has a cell differentiation inducing action.

[0007]

2. Description of the Related Art 1α, 25-dihydroxyvitamin D ₂
And a method for producing the 24-position epimer is a method in which a 22-aldehyde derivative of a steroid in which the diene moiety is protected is used as a starting material, and the 5,7-position in which the 25-position is protected by acetal.
A method of producing a diene derivative by subjecting it to a reaction process such as ultraviolet irradiation, thermal isomerization, oxidation at the 1-position, and deprotection (see JP-T-60-501261);
E) -5,7,22-Ergostatriene-1α, 3β
-Diol diacetate as a starting material, via reaction steps such as protection of 5,7-diene, ozonolysis, coupling of the generated aldehyde compound and sulfone compound, and deprotection of the protective group of 5,7-diene. (22
E) -5,7,22-Ergostatriene-1α, 3
There is known a method of irradiating β, 25-triol or its 24-position epimer with ultraviolet rays to thermally isomerize the product (see JP-A-2-36166).

[0008]

In the above-mentioned conventional method, the 1α-hydroxy provitamin D ₂ derivative is irradiated with ultraviolet rays, and the obtained 1α-hydroxy provitamin D ₂ derivative is isomerized by thermal energy. Thus, it is converted into a 1α-hydroxyvitamin D ₂ derivative.

With respect to vitamin D ₂ derivatives, conversion of provitamin to previtamin by ultraviolet irradiation is an equilibrium reaction between previtamin and provitamin as a raw material and isomers of the previtamin. Tend to increase the pre-vitamin selectivity.

Therefore, even when industrially producing a 1α-hydroxyvitamin D ₂ derivative, a method for suppressing the conversion rate to previtamin is kept low, so that separation of provitamin as a raw material from previtamin or vitamin is performed. It becomes a problem.

However, the main object of the present invention is to provide 1α-
An object of the present invention is to provide an industrially advantageous method for producing a hydroxyvitamin D ₂ derivative. Other objects and advantages of the present invention will become apparent from the following description.

[0012]

According to the present invention, a compound represented by the general formula (II):

[0013]

Embedded image

(Wherein R ¹ represents an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, and A ² represents a compound represented by the general formula (b)

[0015]

Embedded image

Wherein R ² and R ³ each represent a lower alkyl group or a trifluoromethyl group, or together with the carbon atom to which they are attached, represent a carbocyclic ring , X ² and Y ² each represent a hydrogen atom, a fluorine atom, a methyl group, a hydroxyl group or a protected hydroxyl group, and n represents an integer of 1 to 4.
Irradiating the alkoxycarbonyloxy provitamin D ₂ derivative with ultraviolet light to obtain a compound represented by the general formula (III):

[0017]

Embedded image

[0018] (wherein, R ¹ and A ² is as defined above) yielding 1α- alkoxycarbonyloxy previtamin D ₂ derivative represented by the heat the 1α- alkoxycarbonyloxy previtamin D ₂ derivative General formula (IV) by isomerization by energy

[0019]

Embedded image

[0020] (wherein, R ¹ and A ² is as defined above) is converted to 1α- alkoxycarbonyloxy vitamin D ₂ derivative represented by and then the 1α- alkoxy 1α-position carbonyl oxy vitamin D ₂ derivative -
The 1α-hydroxyvitamin D ₂ derivative represented by the general formula (I) and the unreacted 1α-alkoxycarbonyloxyprooxy compound represented by the general formula (II) are removed by removing the OCOR ¹ group and, if necessary, the protecting group for the hydroxyl group. yielding a mixture containing vitamin D ₂ derivative, the from the mixture 1α- hydroxyvitamin D ₂ derivative and the 1α- alkoxycarbonyloxy provitamin D ₂
There is provided a method for producing a 1α-hydroxyvitamin D ₂ derivative represented by the above general formula (I), wherein the derivatives are separated from each other (hereinafter referred to as method A).

According to the present invention, 1α-alkoxycarbonyloxyprovitamin D represented by the general formula (II)
Irradiating the ₂ derivative with ultraviolet light to produce a 1α-alkoxycarbonyloxy previtamin D ₂ derivative represented by the general formula (III), and isomerizing the 1α-alkoxycarbonyloxy previtamin D ₂ derivative by thermal energy; 1α- represented by the general formula (IV)
A mixture containing an alkoxycarbonyloxyvitamin D ₂ derivative and an unreacted 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the above general formula (II) is produced.
The α-alkoxycarbonyloxy provitamin D ₂ derivative is separated as a crystal, which is recycled and reused.
From the remaining crude 1α-alkoxycarbonyloxyvitamin D ₂ derivative represented by the general formula (IV),
The 1α-hydroxyvitamin D ₂ derivative represented by the general formula (I) and the remaining unreacted 1α-alkoxycarbonyloxy group represented by the general formula (II) are obtained by removing the OCOR ¹ group and, if necessary, the protecting group for the hydroxyl group. Producing a mixture containing provitamin D ₂ derivatives,
The 1α-hydroxyvitamin D ₂ derivative and the 1α-alkoxycarbonyloxy provitamin D ₂ derivative are separated from the mixture, respectively,
wherein the α-alkoxycarbonyloxy provitamin D ₂ derivative is recycled and recycled.
In 1α- manufacturing method of hydroxyvitamin D ₂ derivative represented (hereinafter, referred to as the method B) are provided.

As used herein, the term "lower" means that the group or compound to which this term is attached has at most 6, preferably at most 3, carbon atoms.

In the above general formula, the "alkyl group" may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl Butyl,
Pentyl, hexyl and the like can be mentioned. Further, the “alkenyl group” may also be either linear or branched, and includes, for example, allyl, methallyl, dimethylallyl and the like. The “aryl group” may be monocyclic or polycyclic, and includes, for example, phenyl, naphthyl and the like. The aryl group may be appropriately substituted with 1 to 3 substituents, and examples of the substituent include halogen atoms such as chloro and bromo; lower alkyl groups such as methyl and ethyl; methoxy, ethoxy and the like. Lower alkoxy group; nitro group and the like. Thus, specific examples of such substituted aryl groups include, for example, p-chlorophenyl, p-bromophenyl, p-
Methylphenyl, p-nitrophenyl and the like are included.
An "aralkyl group" is an aryl-alkyl group in which the aryl and alkyl moieties each have the meaning described above, and includes, for example, benzyl, phenethyl and the like. The aryl part of the aralkyl group may be appropriately substituted by the same substituents as described for the aryl group. Examples of the substituted aralkyl group include p-bromobenzyl, p-nitrobenzyl, p-chlorobenzyl and the like. Benzyl, p-methoxybenzyl and the like.
The “carbocyclic ring” formed by R ² and R ³ together with the carbon atom to which they are attached can be preferably a 3- to 6-membered ring, especially a 3- to 5-membered ring, for example, cyclopropane Ring, cyclobutane ring, cyclopentane ring, cyclohexane ring and the like.

In the above general formula, the hydroxyl-protecting group in the “protected hydroxyl group” may be any hydroxyl-protecting group which can be removed by, for example, solvolysis in the field of organic chemistry, For example, acyl groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, benzoyl, monochloroacetyl, trifluoroacetyl; methoxycarbonyl, ethoxycarbonyl, lower alkoxycarbonyl groups such as isopropoxycarbonyl; trimethylsilyl, triethylsilyl, Triisopropylsilyl, t
trisubstituted organic silyl groups such as tert-butyldimethylsilyl and tert-butyldiphenylsilyl; alkoxyalkyl groups which may have a substituent such as methoxymethyl, methoxyethoxymethyl, 1- (ethoxy) ethyl and methoxyisopropyl A tetrahydrofuranyl group,
And a tetrahydropyranyl group. X ¹ , X ² ,
“Protected hydroxyl group” which Y ¹ and Y ² can represent respectively
As the protecting group in, a trisubstituted organic silyl group, an optionally substituted alkoxyalkyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group are particularly preferred.

Thus, the above general formulas (I) to (I)
In V), R ¹ is preferably a lower alkyl group, and A ¹ and A ² are each preferably selected from the group consisting of groups represented by the following formulas.

[0026]

Embedded image

Hereinafter, the method of the present invention will be described in more detail.

One major feature of the method of the present invention is that 1α
The hydroxyl group at the 3-position is substituted with a -OOCOR ¹ group (hereinafter sometimes referred to as an alkoxycarbonyloxy group), and the hydroxyl group at the 3β-position is in a free state (that is, unprotected). A novel 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the general formula (II) [hereinafter referred to as compound (II)] which has not been described in the above-mentioned literature. .

By using such a compound (II) as a starting material, the method of the present invention provides a method for removing unreacted compound (II) in any step thereof from a reaction mixture, for example, by treatment with methanol (or methanol rinse). By an extremely simple operation of treating the compound (II) with a poor solvent such as diethyl ether treatment (or diethyl ether rinsing), it can be separated as crystals, and can be recycled and reused as a starting material. Has great advantages.

In the first step of the method A of the present invention, the compound (II) as a starting material is irradiated with ultraviolet rays, and the compound represented by the general formula (II)
This is a step of producing a 1α-alkoxycarbonyloxy previtamin D ₂ derivative (hereinafter sometimes referred to as compound (III)) represented by I).

As the ultraviolet light used for this ultraviolet irradiation, generally, an ultraviolet light having a wavelength in the range of about 200 nm to about 310 nm, preferably in the range of about 260 nm to about 310 nm is suitable. As a light source for ultraviolet irradiation, any light source can be used as long as it emits light containing ultraviolet light having a wavelength within the above range, for example, a high-pressure mercury lamp, a low-pressure mercury lamp, or the like. be able to.

The reaction in the first step is preferably carried out in a solvent. Examples of the solvent include hydrocarbon solvents such as hexane, heptane, cyclohexane, ligroin, benzene, toluene and xylene;
Halogenated hydrocarbon solvents such as chlorobenzene, carbon tetrachloride, 1,2-dichloroethane and 1,2-dibromoethane; ether solvents such as diethyl ether, tetrahydrofuran, dioxane and ethyl cellosolve; alcohols such as methanol, ethanol and propanol A system solvent or the like is used. The used amount can be usually about 50 to 10000 times the weight of compound (II). The reaction is usually carried out at a temperature in the range of about -20C to about 120C, preferably at a temperature in the range of about -10C to about 20C. This reaction is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.

The above-mentioned conversion reaction of compound (II) into compound (III) by irradiation with ultraviolet light comprises compound (II) and compound (II)
An equilibrium reaction between compound (III) and an isomer of compound (III) such as by-produced taxosterol. Therefore, when the conversion of the compound (II) by ultraviolet irradiation is suppressed to a low level, the selectivity of the compound (III), that is, the yield of the compound (III) relative to the consumed compound (II) can be improved.

Therefore, in order to industrially and efficiently produce the desired 1α-hydroxyvitamin D ₂ derivative represented by the general formula (I) [hereinafter sometimes referred to as compound (I)], the compound It is extremely important to keep the conversion of (II) low and to recover and recycle unreacted compound (II). As described above, the compound (II) used as a starting material in the present invention can be easily separated and recovered from the reaction mixture in any step of the method of the present invention by a simple operation (for example, crystallization, chromatography, etc.), and recycled. It has an extremely important industrial advantage that it can be reused.

Thus, in the method of the present invention, the irradiation of the compound (II) with ultraviolet light is carried out when the conversion of the compound (II) is 60%.
, Preferably within the range of 5 to 50%, more preferably within the range of 20 to 50%.

Compound (III) formed in the above first step
Can be subjected to the next thermal isomerization reaction in the second step after it has been partially removed without separation from the reaction mixture in some cases. However, in some cases,
Although it is possible to subject compound (III) to the second step after separating it from the reaction mixture, it is advantageous to carry out the next step as it is without industrial separation.

The isomerization reaction of compound (III) with thermal energy can be carried out usually at a temperature in the range of about 0 ° C. to about 120 ° C., preferably at a temperature in the range of about 20 ° C. to about 80 ° C. . The reaction follows the first step,
It can be carried out in the same solvent as used in the first step. This reaction is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.

A 1α-alkoxycarbonyloxyvitamin D ₂ derivative represented by the general formula (IV) formed by thermal isomerization of the above compound (III) [hereinafter referred to as compound (I
V) is subjected to a elimination reaction of the 1α-position alkoxycarbonyl group (OCOR ¹ ) in the third step.

In this elimination reaction, for example, unreacted compound (II) was not separated and removed from the reaction mixture of the second step in advance, but, for example, the solvent was at least partially removed as necessary from the reaction mixture. The reaction can be carried out on the reaction mixture. The reason is that the compound (IV) contained in the reaction mixture from the second step and the unreacted compound (I
There is a difference in the ease with which the 1α-alkoxycarbonyl group (OCOR ¹ ) is released from each compound of the compound (I) (the compound (I
The 1α-alkoxycarbonyl group in I) is more difficult to leave than the 1α-alkoxycarbonyl group in compound (IV)). Therefore, by appropriately selecting the conditions for the above-mentioned elimination reaction, it is possible to select from compound (IV). Since the 1α-alkoxycarbonyl group can be eliminated from the reaction mixture, and the compound (II) can be recovered from the reaction mixture substantially as it is and can be recycled and reused. It is.

The above-mentioned elimination reaction of the 1α-alkoxycarbonyl group can be usually carried out by solvolysis. Specifically, in a lower alkanol such as methanol, ethanol, or propanol, the reaction is performed using an alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, or potassium carbonate or an aqueous solution thereof. Among them, it is preferable to use alkali-containing methanol which may contain water, particularly lithium hydroxide-containing methanol. The amount of such alkali used is
In general, a small amount such as a catalyst amount is sufficient, but if necessary, an amount up to about 30 equivalents per 1 mol of the compound (IV) can be used. Generally, the alkali is the compound (IV)
Within the range of 0.1 to 20 equivalents per mole, especially 0.5 to
It is convenient to use within the range of 15 equivalents.

This elimination reaction is usually carried out at a temperature within the range of about 0 ° C. to about 80 ° C., preferably at a temperature within the range of about 10 ° C. to about 50 ° C.

The compound (I) thus obtained has two hydroxyl groups at the 1α-position and the 3β-position both in a free state,
Since there is a great difference in properties such as chromatography and crystallinity from the unreacted compound (II) having an alkoxycarbonyloxy group at the 1α-position, separation between the two compounds is extremely easy.

The compound (I) and the unreacted compound (II) can be separated and purified from the reaction mixture by chromatography such as liquid chromatography, by crystallization, or by a combination of both. .

The unreacted compound (II) is easily crystallized and can be easily precipitated as crystals by adding, for example, methanol, diethyl ether or the like to the reaction mixture. Therefore, compound (IV) in the third step
When the alkali-containing methanol is used in the dealkoxycarbonylation reaction of the compound, the unreacted compound (II) can be crystallized simultaneously with the solvolysis of the compound (IV), which is extremely advantageous in the reaction operation. .

Separation and purification of the compound (I) from the mother liquor after crystallization are carried out in the same manner as the method generally used for separation and purification of organic compounds. For example, the reaction mixture is neutralized, concentrated if necessary under reduced pressure, added with water, extracted with a solvent such as ethyl acetate, diethyl ether, methylene chloride, etc. And concentrated under reduced pressure. The resulting residue is purified by recrystallization, chromatography, etc. to obtain compound (I).

When X ¹ and / or Y ¹ represents a protected hydroxyl group, the compound (I) can be subjected to a elimination reaction of the hydroxyl-protecting group, if necessary, whereby X ¹
And / or can be converted to the corresponding compound (I) wherein Y ¹ represents a hydroxyl group. The elimination reaction of the hydroxyl-protecting group can be carried out by a method known per se depending on the type of the protecting group. For example, when the protecting group is an acyl group or a lower alkoxycarbonyl group, the elimination reaction can be carried out under the same conditions as the elimination reaction of the 1α-alkoxycarbonyl group, and in an inert solvent such as tetrahydrofuran or diethyl ether, It can also be carried out by reacting a nucleophile such as lithium aluminum hydride, methyllithium, butyllithium and the like at a temperature in the range of 0 ° C to about 80 ° C. When the protecting group is a trisubstituted organic silyl group, the elimination reaction can be performed by reacting a fluorine ion such as tetrabutylammonium fluoride or cesium fluoride in an inert solvent such as tetrahydrofuran or acetonitrile. When the protecting group is an alkoxyalkyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group which may have a substituent, the elimination reaction is performed in tetrahydrofuran-water, tetrahydrofuran-
The reaction can be carried out by reacting an acid catalyst such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate or acetic acid in a solvent such as ethanol.

On the other hand, the unreacted compound (II) separated and recovered from the reaction mixture in the third step can be circulated to the first step and reused.

According to the above-mentioned method A of the present invention, the 1α-hydroxyvitamin D of the active form represented by the general formula (I) is obtained at a much higher efficiency and higher yield than the above-mentioned conventional method.
_Two derivatives can be produced.

The method B of the present invention is the same as the method A described above.
The reaction mixture obtained in the second step is treated with a poor solvent such as methanol or diethyl ether to separate the compound (II) as crystals from the mixture, circulate it to the first step, and remove the remaining crude The compound (IV) is treated in the same manner as in the third step of the method A to remove the 1α-alkoxycarbonyl group (OCOR ¹ ) and optionally a hydroxyl-protecting group from the compound (IV), thereby producing the compound (I) Compound (I) and compound (II) are separated from the reaction mixture containing unreacted compound (II) remaining as described above, and compound (II) separated and recovered is recycled to the first step. 5 is a modification of the method A of the present invention.

Thus, each step in the method B of the present invention is basically the first step of the method A, except for the above points.
The operation can be performed in the same manner as in the second and third steps.

In the treatment of the reaction mixture obtained in the second step with a poor solvent such as methanol or diethyl ether, the solvent is usually removed, if necessary, at least partially from the reaction mixture. And the like, and the unreacted compound (II) contained therein is precipitated as crystals. The amount of the poor solvent used in this treatment is not strictly limited, and can be varied over a wide range depending on the type of the compound (II), the type of the reaction solvent, and the like. V / W), preferably 20 to 1
It can be in the range of 00 times (V / W). When the poor solvent is methanol, the used methanol contains alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate, particularly preferably lithium hydroxide or an aqueous solution thereof. be able to. The concentration of these alkalis in methanol or methanol water is generally in the range of 0.01 to 5% by weight, preferably 0.1 to 1% by weight. Through the use of such alkali-containing methanol,
By the methanol treatment, 1α-
A part of the elimination reaction of the alkoxycarbonyl group can also be used. The treatment with the poor solvent can be usually performed at room temperature, but can be performed with cooling if necessary.

The compound (II) which precipitates as a crystal in the reaction mixture by the treatment with the poor solvent is separated and recovered by a usual method, and circulated to the first step.

On the other hand, after separating the compound (II),
A mixture containing the main amount of compound (IV) and a small amount of unreacted compound (II) remaining without crystallization remains. This mixture is subjected to the same operation as in the third step of the above-mentioned method A, whereby the unreacted compound (II) is separated and recovered, and the desired compound (I) is obtained. The recovered compound (II) is reused by circulating in the first step.

According to the method B of the present invention described above, the compound (II) as a starting material is reused without waste, and it is extremely efficient and in a high yield, and the 1α-hydroxyvitamin D represented by the general formula (I) is obtained. _Two derivatives can be produced.

The compound (II) used as a starting material in the above-mentioned method of the present invention and the intermediately formed compounds (III) and (IV) are all novel compounds which have not been described in the conventional literature. is there.

Compound (II) has the following general formula (V)

[0057]

Embedded image

(Wherein, R ⁴¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and R ¹ is as defined above) as a raw material, and a side chain having a double bond is obtained from this compound. It can be produced according to a known method of introducing at position 22.

In the above method, when a compound in which R ⁴¹ is a protecting group for a hydroxyl group is used as a raw material, a compound (II) in which R ⁴¹ in which the protecting group is automatically eliminated by a reagent to be used is a hydrogen atom. ) May be obtained. Also R
^When the compound (II) in which ⁴¹ is a hydroxyl-protecting group is obtained, the above-mentioned hydroxyl-protecting group can be selectively used by employing a conventionally known protecting-group elimination condition from the compound (II). To obtain a compound (II) in which R ⁴¹ is a hydrogen atom.

The separation and purification of the compound (II) thus obtained from the reaction mixture can be carried out by the usual separation of organic compounds,
It is carried out in the same manner as the method used in the purification. For example, the reaction mixture is poured into an aqueous ammonium chloride solution or water, extracted with an organic solvent such as diethyl ether, ethyl acetate, methylene chloride, and the like.The extract is washed with brine, dried over anhydrous sodium sulfate, concentrated, and concentrated. This is carried out by obtaining a product and purifying the crude product by recrystallization, chromatography or the like.

The compound represented by the general formula (V) is a compound known per se, and can be produced according to a method for producing a known compound [for example, JP-A-3-14129.
No. 3].

[0062]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but it should be understood that the scope of the present invention is not limited to these Examples.

Example 1 (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25
-500 mg of diol is used for measuring the fatty acid value and the peracid value of diethyl ether 500 m (sold by Wako Pure Chemical Industries, Ltd.).
The resulting solution was irradiated with ultraviolet rays for 4 minutes using a 400 W high-pressure mercury lamp under ice cooling while passing argon gas through the resulting solution. The reaction mixture was concentrated under reduced pressure, and the obtained concentrated solution was dissolved in 100 ml of diisopropyl ether (purification by distillation in the presence of sodium-benzophenone ketyl), and the mixture was refluxed for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure.
and 25 ml of methanol were added, followed by stirring at room temperature for 3 hours. The crystals were filtered and washed with cold methanol. The crystals were dried under reduced pressure and unreacted (24R, 22E) -1α-
(Methoxycarbonyloxy) ergosta-5,7,2
245 mg of 2-triene-3β, 25-diol was recovered. The combined filtrate and washings were concentrated and purified by silica gel column chromatography to give unreacted (2
4R, 22E) -1α- (methoxycarbonyloxy)
A fraction containing 77 mg of ergosta-5,7,22-triene-3β, 25-diol and a vitamin was obtained, and the fraction containing the vitamin was further purified by high performance liquid chromatography to show the following physical property values (24R, 22
E) -9,10-Seco Ergosta-5,7,10 (1
9), 57.1 mg of 22-tetraene-1α, 3β, 25-triol were obtained [Yield: consumed (24R, 2
2E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25-diol 36%]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.56 (s, 3H), 0.96 (d, 3H, J = 6.
9 Hz), 1.01 (d, 3H, J = 6.5 Hz),
1.12 (s, 3H), 1.16 (s, 3H), 4.2
2 (brm, 1H), 4.43 (brm, 1H), 4.
99 (brs, 1H), 5.29 (m, 2H), 5.3
1 (brs, 1H), 5.99 (d, 1H, J = 11.
2 Hz), 6.37 (d, 1H, J = 11.2 Hz)

Example 2 500 mg of 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (methoxycarbonyloxy) pregna-5,7-dien-3β-ol was prepared by subjecting 500 mg of fat and oil acid value and peracid value to 500 mg. The obtained solution was dissolved in 500 ml of diethyl ether for price measurement (available from Wako Pure Chemical Industries, Ltd.), and the obtained solution was irradiated with ultraviolet rays for 4 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. The reaction mixture was concentrated under reduced pressure, and the obtained concentrated solution was dissolved in 60 ml of diisopropyl ether (distillation and purification in the presence of sodium-benzophenone ketyl), and the mixture was refluxed for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was added with 2.5 ml of a 1N aqueous solution of lithium hydroxide and 25 ml of methanol.
and stirred at room temperature for 190 minutes. The reaction solution was neutralized with dilute hydrochloric acid under ice-cooling, and one drop of aqueous sodium bicarbonate was added, followed by filtration. The crystals are washed with cold methanol and dried under reduced pressure to give unreacted 2
270 mg of 0- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (methoxycarbonyloxy) pregna-5,7-dien-3β-ol was recovered. The combined filtrate and washings were concentrated under reduced pressure, water was added to the resulting residue and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel column chromatography, unreacted 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (methoxycarbonyloxy) pregna-5,7-diene-
82.3 mg of 3β-ol and 82.3 mg of a mixture mainly containing vitamins were obtained. The mixture containing vitamins was purified by high performance liquid chromatography to give 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -9,10-secopregna-5 having the following physical properties.
7,10 (19) -triene-1α, 3β-diol 5
8.4 mg [yield: 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α consumed]
-(Methoxycarbonyloxy) pregna-5,7-dien-3β-ol 36%]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 1.01 (d, 3H), 4.2
0 (brm, 1H), 4.40 (m, 1H), 4.43
(Brm, 1H), 5.01 (brs, 1H), 5.3
3 (m, 3H), 6.03 (d, 1H), 6.37
(D, 1H)

Example 3 1α- (methoxycarbonyloxy) ergosta-5,
1.45 g of 7,22-trien-3β-ol was mixed with a hexane-diethyl ether mixed solution (volume ratio: 9: 1) 1500
The obtained solution was divided into about 500 ml, and each solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas through each solution. The reaction mixtures were combined and concentrated under reduced pressure to about 300 ml. This solution was heated and refluxed for 3 hours under an argon atmosphere. After the reaction mixture was concentrated under reduced pressure, 8 ml of methanol was added to the residue, and the mixture was stirred at a temperature in the range of -10 ° C to -5 ° C for 15 minutes. The precipitate was separated by filtration, washed twice with 3 ml of ice-cooled methanol, and dried under reduced pressure to obtain 1α- (methoxycarbonyloxy) ergosta.
682 mg of 5,7,22-trien-3β-ol was recovered. 10 ml of methanol and 2.5 ml of a 1 N aqueous solution of lithium hydroxide were added to the crystal mother liquor, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1 N hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. Add water to the residue,
After extraction with ethyl acetate, the extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and unreacted 1α- (methoxycarbonyloxy) ergosta
Mixture 220 mainly comprising 61 mg of 5,7,22-trien-3β-ol and 1α-hydroxyvitamin D ₂
mg [purity 93.5%]. The mixture was purified by high performance liquid chromatography to obtain 198 mg of 1α-hydroxyvitamin D ₂ having the same physical property values as those in the literature [Yield: 1α- (methoxycarbonyloxy) ergosta-5,7,22 consumed. -32% relative to trien-3 [beta] -ol].

Example 4 (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25
-300 mg of diol was dissolved in 300 ml of diethyl ether, and the resulting solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. After adding about 100 ml of benzene to the reaction mixture,
It concentrated under reduced pressure until it became about 100 ml. The reaction mixture thus obtained was heated and refluxed for 2 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was washed with diethyl ether, and then purified by silica gel column chromatography to obtain unreacted (24R,
175 mg of 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25-diol was recovered and unreacted (24R, 22E) -1
α- (methoxycarbonyloxy) ergosta-5,
7,22-triene-3β, 25-diol and (24
R, 22E) -1α- (methoxycarbonyloxy)-
9,10-Seco Ergosta-5,7,10 (19), 2
81 mg of a mixture containing 2-tetraene-3β, 25-diol was obtained. This mixture was suspended in 3.7 ml of methanol, and 0.37 ml of a 1 N aqueous lithium hydroxide solution was added to the obtained suspension, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (24R, 22E) -1α-
(Methoxycarbonyloxy) ergosta-5,7,2
21 mg of 2-triene-3β, 25-diol and 2
47 mg [purity: 65.0%] of a mixture mainly containing 4-epi-1α, 25-dihydroxyvitamin D ₂ was obtained. This mixture was purified by high performance liquid chromatography, and showed the same physical property values as those obtained in Example 1.
30 mg of 1α, 25-dihydroxyvitamin D ₂ was obtained [purity 99.5%, yield: consumed (24R, 22E)]
-1α- (methoxycarbonyloxy) ergosta
33% based on 5,7,22-triene-3β, 25-diol].

Example 5 (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25
-300 mg of diol was dissolved in 300 ml of diethyl ether, and the resulting solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. After adding about 100 ml of benzene to the reaction mixture,
It concentrated under reduced pressure until it became about 100 ml. The reaction mixture thus obtained was heated and refluxed for 2 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was suspended in 15 ml of methanol, and 1.5 ml of a 1 N aqueous solution of lithium hydroxide was added to the resulting suspension, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was rinsed with methanol, and (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-
180 mg of triene-3β, 25-diol was recovered. The mother liquor was purified by silica gel column chromatography to give (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3.
β, 25-diol 30 mg and 24-epi-1α,
25-dihydroxyvitamin D ₂ mixture mainly containing 48
mg [purity: 80.3%]. This mixture was purified by high performance liquid chromatography to obtain 25 mg of 24-epi-1α, 25-dihydroxyvitamin D ₂ having the same physical property values as those obtained in Example 1 [purity 99.1].
%, Yield: consumed (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-
32% based on triene-3β, 25-diol].

Example 6 (24R, 22E) -1α-ethoxycarbonyloxy-25- (tetrahydrofuran-2-yloxy) ergosta-5,7,22-trien-3β-ol 506
mg was dissolved in 500 ml of a hexane-diethyl ether mixed solution (volume ratio of 1 to 1), and the obtained solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. The reaction mixture was concentrated under reduced pressure, and 5 ml of diethyl ether was added to the residue.
For 5 minutes. The precipitate was separated by filtration, washed twice with 2 ml of ice-cooled diethyl ether, and dried under reduced pressure to give (24R, 22E) -1α-ethoxycarbonyloxy-25- (tetrahydrofuran-
292 mg of 2-yloxy) ergosta-5,7,22-trien-3β-ol were recovered. The crystal mother liquor was concentrated under reduced pressure, 100 ml of benzene was added to the residue, and the mixture was refluxed for 2 hours under an argon atmosphere. The reaction mixture thus obtained was concentrated under reduced pressure, and methanol was added to the residue.
Then, 0.5 ml of a 1N aqueous solution of lithium hydroxide and 0.5 ml of a 1N lithium hydroxide aqueous solution were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was neutralized with 1 N hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (24R, 22E) -1α-
38 mg of ethoxycarbonyloxy-25- (tetrahydrofuran-2-yloxy) ergosta-5,7,22-trien-3β-ol and 24-epi-1α-
53 mg of a mixture mainly containing hydroxy-25- (tetrahydrofuran-2-yloxy) vitamin D ₂ [purity:
82.1%]. This mixture was purified by high performance liquid chromatography to give 24-epitaxy having the following physical properties.
1α-hydroxy-25- (tetrahydrofuran-2-
Yloxy) of vitamin D ₂ was obtained 56mg. [Purity: 9
8.5%, yield: consumed (24R, 22E) -1α
-Ethoxycarbonyloxy-25- (tetrahydrofuran-2-yloxy) ergosta-5,7,22-36% relative to trien-3β-ol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.56 (s, 3H), 0.98 (s, 3H), 1.0
2 (d, 3H), 1.11 (d, 3H), 1.18
(D, 3H), 3.77 (m, 2H), 4.18-4.
23 (m, 3H), 4.99 (brs, 1H), 5.2
7 to 5.40 (m, 5H), 5.97 (d, 1H, J =
11.1 Hz), 6.37 (d, 1H, J = 11.1H)
z) 35 mg of 24-epi-1α-hydroxy-25- (tetrahydrofuran-2-yloxy) vitamin D ₂
Was dissolved in 4 ml of methanol, 2 mg of pyridinium p-toluenesulfonate was added to the resulting solution, and
Stirred for hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization using diethyl ether to obtain 23 mg of 24-epi-1α, 25-dihydroxyvitamin D ₂ having the same physical property values as those obtained in Example 1.

Example 7 (24S, 22E) -1α-allyloxycarbonyloxy-25- (methoxymethoxy) ergosta-5
615 mg of 7,22-trien-3β-ol was dissolved in 600 ml of diethyl ether, and the obtained solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. Hexane 20 was added to the reaction mixture.
0 ml was added, and the mixture was concentrated under reduced pressure to about 200 ml. The reaction mixture thus obtained was heated under reflux for 2 hours under an argon atmosphere, then the reaction mixture was concentrated under reduced pressure, the residue was suspended in 30 ml of methanol, and 1N hydroxide was added to the resulting suspension. Add 3 ml of lithium aqueous solution,
Stirred at room temperature for 2 hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. The residue was poured into water and extracted with ethyl acetate. Wash the extract with saline,
After drying over sodium sulfate, it was concentrated under reduced pressure.
The residue was rinsed with methanol, (24S, 22
E) -1α-allyloxycarbonyloxy-25-
320 mg of (methoxymethoxy) ergosta-5,7,22-trien-3β-ol was recovered. The mother liquor was purified by silica gel column chromatography.
S, 22E) -1α-allyloxycarbonyloxy-
25- (methoxymethoxy) ergosta-5,7,22
82 mg of a mixture mainly containing 55 mg of -trien-3β-ol and 1α-hydroxy-25- (methoxymethoxy) vitamin D ₂ were obtained [purity 79.8%]. This mixture was purified by high performance liquid chromatography to obtain 62 mg of 1α-hydroxy-25- (methoxymethoxy) vitamin D ₂ having the following physical properties [purity: 98.9].
%, Yield: 30% based on (24S, 22E) -1α-allyloxycarbonyloxy-25- (methoxymethoxy) ergosta-5,7,22-trien-3β-ol consumed]. ¹ H- NMR spectrum (90 Hz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 0.99 (d, 3H, J = 6.
8 Hz), 1.03 (d, 3H, J = 6.5 Hz),
1.12 (s, 3H), 1.17 (s, 3H), 3.4
0 (s, 3H), 4.23 (brm, 1H), 4.43
(Brm, 1H), 4.59 (s, 2H), 5.00
(Brs, 1H), 5.31 (m, 3H), 5.99
(D, 1H, J = 10.7 Hz), 6.37 (d, 1
H, J = 10.7 Hz) 41 mg of 1α-hydroxy-25- (methoxymethoxy) vitamin D ₂ was dissolved in 5 ml of tetrahydrofuran, and the resulting solution was added with 1 m of 5N hydrochloric acid.
was added and stirred at room temperature for 30 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization using diethyl ether to give 1α, 25-dihydroxyvitamin D ₂ having the following physical properties.
mg was obtained. ¹ H- NMR spectrum (90 Hz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 1.00 (d, 3H, J = 6.
8 Hz), 1.03 (d, 3H, J = 6.6 Hz),
1.12 (s, 3H), 1.17 (s, 3H), 4.2
3 (brm, 1H), 4.43 (brm, 1H), 5.
00 (brs, 1H), 5.32 (m, 3H), 6.0
0 (d, 1H, J = 10.7 Hz), 6.37 (d, 1
H, J = 10.6 Hz)

Example 8 (24S, 22E) -1α- (allyloxycarbonyloxy) ergosta-5,7,22-triene-3β,
500 mg of 25-diol in 500 ml of diethyl ether
The resulting solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high pressure mercury lamp under ice cooling while passing argon gas through the resulting solution. The reaction mixture was concentrated under reduced pressure, 200 ml of benzene was added to the residue, and the mixture was refluxed for 2 hours under an argon atmosphere. The reaction mixture thus obtained is concentrated under reduced pressure, and the residue is mixed with an ethanol-water mixture (volume ratio 95: 5).
10 ml was added, and the mixture was stirred under ice cooling for 20 minutes. The precipitate was separated by filtration, washed twice with 2 ml of ice-cooled ethanol, and dried under reduced pressure to obtain (24S, 22E) -1α-.
(Allyloxycarbonyloxy) ergosta-5,
188 mg of 7,22-triene-3β, 25-diol
Was recovered. The crystal mother liquor was concentrated under reduced pressure, and 32 ml of methanol and 3.5N aqueous 1N lithium hydroxide solution were added to the residue.
Then, the mixture was stirred for 1 hour under ice cooling. 1 reaction mixture
The mixture was neutralized with normal hydrochloric acid and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Wash the extract with saline,
After drying over sodium sulfate, it was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to give (24S, 22E) -1α- (allyloxycarbonyloxy) ergosta-5,7,22-triene-3.
92.1 mg of a mixture mainly containing 71.0 mg of β, 25-diol and 1α, 25-dihydroxyvitamin D ₂
[Purity: 88.3%] was obtained. This mixture was purified by high performance liquid chromatography to give 1α, 25-dihydroxyvitamin having the same physical properties as those obtained in Example 7.
The D ₂ to give 61.0 mg [purity: 99.0%, yield: was consumed (24S, 22E) -1? (Allyloxycarbonyloxy) ergosta 5,7,22 triene-3.beta, 25- 30% based on diol].

Example 9 488 mg of 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (ethoxycarbonyloxy) pregna-5,7-dien-3β-ol was dissolved in 500 ml of diethyl ether. The resulting solution was irradiated with ultraviolet light for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. The reaction mixture was concentrated under reduced pressure, 300 ml of benzene was added to the residue, and the mixture was refluxed for 2 hours under an argon atmosphere. The reaction mixture thus obtained was concentrated under reduced pressure, 10 ml of a methanol-water mixed solution (volume ratio: 9: 1) was added to the residue, and the mixture was stirred for 10 minutes under ice cooling. The precipitate was separated by filtration, and ice-cooled methanol 5 ml
, And dried under reduced pressure to give 20-
(3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (ethoxycarbonyloxy) pregna
263.8 mg of 5,7-dien-3β-ol was recovered. The crystal mother liquor was concentrated under reduced pressure, and methanol was added to the residue.
Then, 3.25 ml of a 1 N aqueous solution of lithium hydroxide was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid, and methanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 20- (3-cyclopropyl-3-hydroxy-
1-propenyl) -1α- (ethoxycarbonyloxy) pregna-5,7-dien-3β-ol 71.5
mg and 20- (3-cyclopropyl-3-hydroxy-1-propenyl) -9,10-secopregna-5.
82.9 mg of a mixture mainly containing 7,10 (19) -triene-1α, 3β-diol were obtained. This mixture was purified by high performance liquid chromatography to give 20- (3-cyclopropyl-3-hydroxy-1-) having the following physical data.
Propenyl) -9,10-secopregna-5,7,10
(19) -Triene-1α, 3β-diol 47.8 m
[purity: 98.2%, yield: 20-consumed]
(3-cyclopropyl-3-hydroxy-1-propenyl) -1α- (ethoxycarbonyloxy) pregna
37% relative to 5,7-dien-3β-ol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 1.01 (d, 3H), 4.2
0 (brm, 1H), 4.40 (m, 1H), 4.43
(Brm, 1H), 5.01 (brs, 1H), 5.3
3 (m, 3H), 6.03 (d, 1H), 6.37
(D, 1H)

Example 10 (22E) -1α-methoxycarbonyloxy-25-
(Triethylsilyloxy) cholesta-5,7,22-
410 mg of triene-3β-ol was dissolved in 400 ml of a hexane-diethyl ether mixed solution (volume ratio: 9: 1), and the resulting solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp under ice cooling while passing argon gas. .
The reaction mixture was concentrated under reduced pressure to about 200 ml. The reaction mixture thus obtained was heated under reflux for 2 hours under an argon atmosphere, concentrated under reduced pressure, and the obtained residue was suspended in 15 ml of methanol. 1.2 ml of lithium aqueous solution is added,
Stirred at room temperature for 4 hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. The residue was poured into water and extracted with ethyl acetate. Wash the extract with saline,
After drying over sodium sulfate, it was concentrated under reduced pressure.
The residue was rinsed with methanol to give (22E) -1α
-Methoxycarbonyloxy-25- (triethylsilyloxy) cholesta-5,7,22-triene-3β-
87.1 mg of all was recovered. The mother liquor was purified by silica gel column chromatography to give (22E) -1α-
96.5 mg of methoxycarbonyloxy-25- (triethylsilyloxy) cholesta-5,7,22-trien-3β-ol and (22E) -25-triethylsilyloxy-9,10-secocholesta-5,7,10
157.7 mg [purity: 87.6%] of a mixture mainly containing (19), 22-tetraene-1α, 3β-diol was obtained. This mixture was purified by high performance liquid chromatography to give 22E-25-triethylsilyloxy-9,10-secocholesta-5,7,10 having the following physical data.
(19), 22-Tetraene-1α, 3β-diol 8
2.4 mg were obtained [purity: 98.8%, yield: spent 22E-1α-methoxycarbonyloxy-25-].
(Triethylsilyloxy) cholesta-5,7,22-
40% relative to trien-3β-ol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) [ delta] (ppm): 0.52 to 0.55 (m, 9H), 0.91 to 1.03
(M, 12H), 1.16 (s, 3H), 1.18
(S, 3H), 4.21 (brm, 1H), 4.43
(Brm, 1H), 5.00 (m, 1H), 5.31
(M, 3H), 6.01 (d, 1H), 6.38 (d,
1H) (22E) -25-triethylsilyloxy-9,10-secocholesta-5,7,1 under argon atmosphere
0 (19), 22-Tetraene-1α, 3β-diol (42.4 mg) was dissolved in tetrahydrofuran (15 ml),
0.8 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride (1M solution) was added to the resulting solution, and 5
Stirred at 0 ° C. for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. Wash the extract with saline,
After drying over sodium sulfate, it was concentrated under reduced pressure.
The residue was purified by high performance liquid chromatography and showed the following physical data of (22E) -9,10-secocholester.
5,7,10 (19), 22-tetraene-1α, 3
30.7 mg of β, 25-triol was obtained. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.52 (s, 3H), 0.91 (d, 3H, J = 6.
4 Hz), 1.19 (s, 6H), 4.21 (brm,
1H), 4.43 (brm, 1H), 5.00 (m, 1
H), 5.31 (m, 3H), 6.01 (d, 1H),
6.37 (d, 1H)

Example 11 (22E) -26-methyl-1α- (phenoxycarbonyloxy) cholesta-5,7,22-triene-3
310 mg of β, 25-diol is added to diethyl ether 30
The resulting solution was irradiated with ultraviolet light for 3 minutes using a 400 W high-pressure mercury lamp under ice cooling while passing argon gas through the resulting solution. The reaction mixture was concentrated under reduced pressure, and 4 ml of an ethanol-water mixture (volume ratio: 9: 1) was added to the residue, followed by stirring for 15 minutes under ice cooling. The precipitate was separated by filtration, washed twice with 1.5 ml of ice-cooled ethanol, and dried under reduced pressure to give (22E) -26-methyl-1α- (phenoxycarbonyloxy) cholesta-5,7,22. 112 mg of -triene-3β, 25-diol were recovered. The crystal mother liquor was concentrated under reduced pressure, 140 ml of benzene was added to the residue, and the mixture was heated under reflux for 3 hours under an argon atmosphere. After leaving the reaction mixture thus obtained at room temperature overnight,
The mixture was concentrated under reduced pressure, and 15 ml of methanol and 0.8 ml of a 1N aqueous solution of lithium hydroxide were added to the residue.
Stirred for hours. The reaction mixture was neutralized with 1N hydrochloric acid, and methanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and (22E)
-26-methyl-1α- (phenoxycarbonyloxy) cholesta-5,7,22-triene-3β, 25-
22.8 mg of diol and (22E) -26-methyl-9,10-secocholesta-5,7,10 (19), 2
67.3 mg of a mixture mainly containing 2-tetraene-1α, 3β, 25-triol were obtained. This mixture was purified by high performance liquid chromatography and showed the following physical data of (22E) -26-methyl-9,10-secocholester.
5,7,10 (19), 22-tetraene-1α, 3
45.2 mg of β, 25-triol was obtained [purity: 9
9.8%, yield: consumed (22E) -26-methyl-1α- (phenoxycarbonyloxy) cholesta
33% based on 5,7,22-triene-3β, 25-diol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.56 (s, 3H), 1.01 (d, 3H), 1.1
8 (s, 3H), 4.23 (brm, 1H), 4.44
(Brm, 1H), 5.00 (brs, 1H), 5.3
2 (m, 3H), 6.00 (d, 1H, J = 11.
0), 6.38 (d, 1H, J = 11.0)

Example 12 (22E) -1α-benzyloxycarbonyloxy-
24- (tert-butyldimethylsilyloxy) cholesta-5,7,22-trien-3β-ol 268 m
g was dissolved in 300 ml of diethyl ether, and the resulting solution was irradiated with ultraviolet rays for 2.5 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. 200 ml of benzene was added to the reaction mixture, and the mixture was concentrated under reduced pressure to about 150 ml. The reaction mixture thus obtained was heated under reflux for 3 hours under an argon atmosphere, concentrated under reduced pressure, washed with diethyl ether, and purified by silica gel column chromatography to obtain unreacted (22E)- 1α-benzyloxycarbonyloxy-24- (tert-butyldimethylsilyloxy) cholesta-5,7,22-trien-3β-ol
0 mg was collected and (22E) -1α-benzyloxycarbonyloxy-24- (tert-butyldimethylsilyloxy) cholesta-5,7,22-triene-3β
-Ol and (22E) -24- (tert-butyldimethylsilyloxy) -9,10-secocholesta-5,
157 mg of a mixture containing 7,10 (19), 22-tetraene-1α, 3β-diol was obtained. This mixture was suspended in 7.5 ml of methanol, and 1 part of the resulting suspension was added.
0.8 ml of a normal aqueous lithium hydroxide solution was added, and the mixture was added at room temperature for 3 hours.
Stirred for hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling,
The methanol was distilled off under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and (22
E) -1α-benzyloxycarbonyloxy-24-
(Tert-butyldimethylsilyloxy) cholester
25.5 mg of 5,7,22-trien-3β-ol and (22E) -24- (tert-butyldimethylsilyloxy) -9,10-secocholesta-5,7,10
56.6 mg of a mixture mainly containing (19), 22-tetraene-1α, 3β-diol was obtained. This mixture was purified by high performance liquid chromatography, and showed the following physical property values of (22E) -24- (tert-butyldimethylsilyloxy) -9,10-secocholesta-5,7,10.
(19), 22-Tetraene-1α, 3β-diol 3
5.2 mg were obtained [purity: 97.7%, yield: spent (22E) -1α-benzyloxycarbonyloxy-24- (tert-butyldimethylsilyloxy) cholesta-5,7,22-triene]. 35% for -3β-ol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.07 (s, 6H), 0.56 (s, 3H), 0.8
8 (s, 9H), 1.00 (d, 3H), 4.22 (b
rm, 1H), 4.39 (m, 1H), 4.42 (br
m, 1H), 5.00 (brs, 1H), 5.30
(M, 3H), 6.02 (d, 1H), 6.37 (d,
1H) 22E-24- (tert-Butyldimethylsilyloxy) -9,10-secocholesta-5,7,10
(19), 22-Tetraene-1α, 3β-diol 1
5.2 mg was dissolved in 7 ml of tetrahydrofuran, and 0.3 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride (1M solution) was added to the obtained solution, and the solution was heated to 50 ° C.
For 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography, and exhibited the following physical properties: 22E-9,10-secocholesta-5,7,10
(19), 8.2 mg of 22-tetraene-1α, 3β, 24-triol was obtained. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 0.99 (d, 3H), 4.2
2 (brm, 1H), 4.39 (m, 1H), 4.42
(Brm, 1H), 5.01 (brs, 1H), 5.3
0 (m, 3H), 6.01 (d, 1H), 6.37
(D, 1H)

Example 13 (24R, 22E) -1α- (isobutoxycarbonyloxy) ergosta-5,7,22-triene-3β-
502 mg of all was dissolved in 500 ml of diethyl ether, and the resulting solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas.
The reaction mixture was concentrated under reduced pressure, and 6.5 ml of an ethanol-water mixture (volume ratio: 9: 1) was added to the residue.
Stirred for minutes. The precipitate was separated by filtration, washed twice with 2.5 ml of ice-cooled ethanol, and dried under reduced pressure to give (24R, 22E) -1α- (isobutoxycarbonyloxy) ergosta-5,7,22-. Triene-3β
-271.4 mg of all were recovered. The crystal mother liquor was concentrated under reduced pressure, 230 ml of benzene was added to the residue, and the mixture was refluxed for 3 hours under an argon atmosphere. The reaction mixture thus obtained was concentrated under reduced pressure, and methanol was added to the residue.
Then, 1.3 ml of 1N aqueous lithium hydroxide solution and 1.3 ml of 1N lithium hydroxide aqueous solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid, and methanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Wash the extract with saline,
After drying over sodium sulfate, it was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to give (24R, 22E) -1α- (isobutoxycarbonyloxy) ergosta-5,7,22-triene-3.
34.9 mg of β-ol and 56.4 mg of a mixture mainly comprising 1α-hydroxyvitamin D ₂ were obtained. This mixture was purified by high performance liquid chromatography, and 49.7 mg of 1α-hydroxyvitamin D ₂ having the following physical property values was obtained.
[Purity: 99.6%, yield: consumed (24
R, 22E) -1α- (isobutoxycarbonyloxy) ergosta-5,7,22-32% based on trien-3β-ol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.56 (s, 3H), 0.83 (dd, 6H, J =
4.4 Hz), 0.93 (d, 3H, J = 6.0H)
z), 1.04 (d, 3H, J = 6.7 Hz), 4.2
3 (brm, 1H), 4.42 (brm, 1H), 5.
00 (m, 1H), 5.21 (m, 2H), 5.32
(M, 1H)

Example 14 1α-Methoxycarbonyloxy-24-homocholesta-5,7,22-triene-3β, 25-diol 50
0 mg of a hexane-diethyl ether mixed solution (volume ratio 9
Pair 1) Dissolve in 500 ml and use a 400 W high-pressure mercury lamp under ice cooling while passing argon gas through the resulting solution.
UV light was applied for a minute. The reaction mixture is concentrated under reduced pressure,
60 ml of benzene was added to the residue, and the mixture was
Heated to reflux for an hour. The reaction mixture thus obtained was concentrated under reduced pressure, the residue was suspended in 25 ml of methanol, 1.25 ml of a 1N aqueous lithium hydroxide solution was added to the resulting suspension, and the mixture was stirred at room temperature for 3 hours. . The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. After the extract was washed with saline and dried over sodium sulfate,
Concentrated under reduced pressure. The residue was rinsed with methanol to give unreacted 1α-methoxycarbonyloxy-24-
Homocholesta-5,7,22-triene-3β, 25-
182 mg of diol were recovered. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain unreacted 1α-methoxycarbonyloxy-24.
-Homocholesta-5,7,22-triene-3β, 25
-Diol 90 mg and 24-homo-9,10-secocholesta-5,7,10 (19), 22-tetraene-
79m mixture mainly containing 1α, 3β, 25-triol
g [89.3% purity]. This mixture was purified by high performance liquid chromatography and exhibited the following physical data.
-Homo-9,10- Secocholesta-5, 7, 10 (1
9), 22-Tetraene-1α, 3β, 25-triol, 60.5 mg [purity: 99.2%, yield: consumed 1α-methoxycarbonyloxy-24-homocholesta-5,7,22-). 30% based on triene-3β, 25-diol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.55 (s, 3H), 1.02 (d, 3H, J = 6.
6 Hz), 1.22 (s, 6H), 2, 32 (dd, 1
H, J = 13 Hz, 7 Hz), 2.60 (dd, 1H,
J = 13 Hz, 3 Hz), 2.83 (dd, 1H, J =
12Hz, 3Hz), 4.23 (m, 1H), 4.43
(M, 1H), 5.00 (brs, 1H), 5.30
(Dd, 1H, J = 15 Hz, 7 Hz), 5.33 (b
rs, 1H), 6.01 (d, 1H, J = 11 Hz),
6.32 (d, 1H, J = 11 Hz)

Example 15 1α-Methoxycarbonyloxy-24-dihomocholesta-5,7,22-triene-3β, 25-diol 5
00 mg was dissolved in 500 ml of a hexane-diethyl ether mixed solution (volume ratio: 9: 1), and the obtained solution was irradiated with ultraviolet rays for 3 minutes using a 400 W high-pressure mercury lamp while cooling with ice while passing argon gas. 100 benzene in the reaction mixture
Then, the mixture was concentrated under reduced pressure to about 50 ml. The reaction mixture thus obtained was heated under reflux for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was suspended in 25 ml of methanol, 1.25 ml of a 1 N aqueous lithium hydroxide solution was added to the obtained suspension, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with dilute hydrochloric acid under ice cooling, and methanol was distilled off under reduced pressure. Add water to the residue,
Extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was rinsed with methanol to collect 197 mg of 1α-methoxycarbonyloxy-24-dihomocholesta-5,7,22-triene-3β, 25-diol.
The mother liquor was purified by silica gel column chromatography, and 98 mg of 1α-methoxycarbonyloxy-24-dihomocholesta-5,7,22-triene-3β, 25-diol and 24-dihomo-9,10-secocholesta-5,7,10 ( 19), 22-tetraene-1α,
A mixture mainly containing 3β, 25-triol was purified by high-performance liquid chromatography and exhibited the following physical data.
Dihomo-9,10-secocholesta-5,7,10 (1
9), 58.1 mg of 22-tetraene-1α, 3β, 25-triol [purity: 99.3%, yield: consumed 1α-methoxycarbonyloxy-24-homocholesta-5,7,22- 32% based on triene-3β, 25-diol]. ¹ H- NMR spectrum (90 MHz , CDCl ₃ , TM
S ) δ (ppm): 0.56 (s, 3H), 1.02 (d, 3H, J = 6.
5 Hz), 1.21 (s, 6H), 2.32 (dd, 1
H, J = 13 Hz, 7 Hz), 2.59 (dd, 1H,
J = 13 Hz, 3 Hz), 2.82 (dd, 1H, J =
12Hz, 3Hz), 4.23 (m, 1H), 4.44
(M, 1H), 5.00 (brs, 1H), 5.30
(Dd, 1H, J = 15 Hz, 7 Hz), 5.33 (b
rs, 1H), 6.01 (d, 1H, J = 11 Hz),
6.32 (d, 1H, J = 11 Hz)

Example 16 13.6 g of (2S)-(2,3-dimethyl-3-tetrahydrofuranyloxybutyl) phenyl sulfone (4
(3.6 mmol) was dissolved in 200 ml of tetrahydrofuran, and 26.4 ml of butyl lithium (1.6 ml) was added at -68 ° C.
5M, hexane solution) was added dropwise. After stirring at the same temperature for 20 minutes, a solution prepared by dissolving 10 g (21.7 mmol) of 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde in 60 ml of tetrahydrofuran is added dropwise, and gradually. To room temperature. After ammonium chloride was added to the reaction solution, it was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Concentrate under reduced pressure,
The obtained residue was purified by silica gel column chromatography to give (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5,7-. 15.4 g of dien-22-ol was obtained (yield 91.6%). (24S) obtained above
-1α, 3β-bis (methoxycarbonyloxy) -2
4-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5,7-diene-22
3 g (5.4 mmol) of -ol was dissolved in 400 ml of tetrahydrofuran, and 400 ml of a saturated disodium hydrogen phosphate / methanol solution and 60 g of disodium hydrogen phosphate were added. After stirring at room temperature for 30 minutes, the mixture was cooled on ice, 50 g of 5% sodium amalgam was added, and stirring was continued for 22 hours. Hexane was added to the reaction solution, decanted, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give (24R, 22E) -1α-methoxycarbonyloxy-25-tetrahydrofuranyloxyergosta-5, having the following physical properties.
702 mg of 7,22-trien-3β-ol was obtained (yield 32.5%). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.64 (s, 3H), 0.94 to 1.05 (m, 9
H), 1.13 (s, 3H), 3.78 (s, 3H),
3.99 (brm, 1H), 4.82 (brs, 1
H), 5.2 to 5.45 (m, 4H), 5.7 to 5.7.
8 (brm, 1H)

Example 17 (24R, 22E) -1α-obtained according to Example 16
Methoxycarbonyloxy-25-tetrahydrofuranyloxyergosta-5,7,22-triene-3β-
70.2 mg (0.126 mmol) of all was dissolved in 10 ml of methanol, 5 mg of pyridinium p-toluenesulfonate was added, and stirring was continued at room temperature for one day. After adding aqueous sodium bicarbonate to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. It is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give (24R, 22E) -1α-methoxycarbonyloxyergosta-5,7,22-triene-3β, 25 having the following physical properties. -52.9 mg of diol were obtained (86.2% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.64 (s, 3H), 0.94 to 1.05 (m, 9
H), 1.13 (s, 3H), 3.78 (s, 3H),
3.99 (brm, 1H), 4.82 (brs, 1
H), 5.21-5.39 (m, 3H), 5.65-
5.68 (brm, 1H)

Example 18 3 ml of diisopropylamine was added to tetrahydrofuran 40
and butyllithium (1.6M at -78 ° C).
Hexane solution (13 ml) was added dropwise. To this solution, a solution of 1.68 g of cyclopropyl methyl ketone dissolved in 10 ml of tetrahydrofuran was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. To this solution, a solution obtained by dissolving 8.28 g (18 mmol) of 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde in 30 ml of tetrahydrofuran was added dropwise at −78 ° C. And stirred for 1 hour. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was heated to room temperature, extracted with diethyl ether, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was treated with 100 ml of chloroform and 200 ml of toluene.
Then, 1.5 g of p-toluenesulfonic acid was added, and the mixture was stirred at 60 ° C for 20 minutes. Ethyl acetate was added to the obtained reaction solution, washed with aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. By concentrating under reduced pressure and purifying the obtained residue by silica gel column chromatography, 1α, 3
β-bis (methoxycarbonyloxy) -20- (3-
5.87 g of cyclopropyl-3-oxo-1-propenyl) pregna-5,7-diene were obtained. 1α, 3β-bis (methoxycarbonyloxy) -20- (3-cyclopropyl-3-oxo-1-propenyl) pregna
To a solution of 5.26 g (10 mmol) of 5,7-diene and 50 ml of tetrahydrofuran was added 25 ml of 0.4 M cerium trichloride hexahydrate in methanol and 15 ml of methanol, and then 1 g of sodium borohydride under ice-cooling. And stirred for 10 minutes. 25 ml of a 1N aqueous solution of lithium hydroxide and 100 ml of methanol were added to this solution, followed by stirring at room temperature for 2 hours. The obtained reaction solution was diluted with water, extracted with methylene chloride, and the extract was washed with brine. After drying over anhydrous sodium sulfate, the mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give 1α- (methoxycarbonyloxy) -20- having the following physical properties.
(3-cyclopropyl-3-hydroxy-1-propenyl) pregna-5,7-dien-3β-ol 3.62
g was obtained. ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.17-0.4 (m, 4H), 0.4-0.6 (m,
1H), 0.64 (s, 3H), 0.9-1.1 (m,
6H), 1.2-2.2 (m, 14H), 2.2-2.
42 (m, 2H), 2.45-2.62 (m, 2H),
3.4-3.5 (m, 1H), 3.79 (s, 3H),
3.92-4.07 (m, 1H), 4.82 (brs,
1H), 5.38 (brs, 1H), 5.4-5.6.
(M, 2H), 5.67 (brs, 1H)

Example 19 In Example 16, (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of (3-tetrahydrofuranyloxybutyl) phenyl sulfone, (2
R)-(2,3-dimethylbutyl) phenylsulfone 4
The reaction and separation and purification were carried out in the same manner except that 3.6 mmol was used to obtain (24R) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23.
-Phenylsulfonylcholesta-5,7-diene-22
Thus, 13.7 g of -ol was obtained (yield: 92%). Then
(24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-2
Instead of 3 g (5.4 mmol) of 5-tetrahydrofuranyloxycholesta-5,7-dien-22-ol, (24R) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonylcole Reaction and separation and purification were carried out in the same manner except that 5.4 mmol of star-5,7-dien-22-ol was used to obtain (24R, 22E) -1α having the following physical properties.
-Methoxycarbonyloxyergosta-5,7,22
-Trien-3β-ol 1.14 g was obtained (yield 45).
%). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.64 (s, 3H), 0.94 to 1.05 (m, 9
H), 1.13 (s, 3H), 3.78 (s, 3H),
3.99 (brm, 1H), 4.82 (brs, 1
H), 5.21-5.39 (m, 3H), 5.67-
5.7 (brm, 1H)

Example 20 In Example 16, 1g, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde was replaced by 1 g (21.7 mmol).
α, 3β-bis (ethoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde 21.7 m
and (24S) -1α, 3β-bis (ethoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholester- 16.1 g of 5,7-dien-22-ol was obtained (yield 92.7%). (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23
Phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5,7-dien-22-ol 5.4 mm
5.4 mmol of (24S) -1α, 3β-bis (ethoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5,7-dien-22-ol instead of ol The reaction and separation and purification were carried out in the same manner except for the presence of (24R, 22E) -1α-
Ethoxycarbonyloxy-25-tetrahydrofuranyloxyergosta-5,7,22-triene-3β-
1.17 g of all were obtained (38% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.63 (s, 3H), 0.93 to 1.02 (m, 9
H), 1.10 to 1.21 (m, 6H), 3.77
(M, 2H), 3.78-4.00 (m, 3H), 4.
82 (brs, 1H), 5.21 to 5.43 (m, 4
H), 5.65 to 5.68 (brm, 1H)

Example 21 In Example 16, (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of (3-tetrahydrofuranyloxybutyl) phenyl sulfone, (2
R)-(2,3-dimethyl-3-methoxymethoxybutyl) phenylsulfone (43.6 mmol) and 1
α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde 10 g (2
1.7 mmol) instead of 1α, 3β-bis (allyloxycarbonyloxy) pregna-5,7-diene-
By performing the reaction and separation and purification in the same manner except that 21.7 mmol of 20-carbaldehyde was used,
15.2 g of (24R) -1α, 3β-bis (allyloxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25- (methoxymethoxy) cholesta-5,7-dien-22-ol was obtained. Rate 87.8
%). (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5
(24R) -1α, 3β-bis (allyloxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25-methoxymethoxycholesta-5,7-diene instead of 5.4 mmol of 7-dien-22-ol −
The reaction and separation and purification were carried out in the same manner except that 5.4 mmol of 22-ol was used to obtain (24S, 22E) -1α-allyloxycarbonyloxy-25- (methoxymethoxy) ergosta having the following physical properties.
1.26 g of 5,7,22-trien-3β-ol was obtained (42% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.64 (s, 3H), 0.94 to 1.06 (m, 9
H), 1.13 (s, 3H), 1.16 (s, 3H),
3.41 (s, 3H), 4.02 (brm, 1H),
4.55-4.83 (m, 5H), 5.09-5.52
(M, 5H), 5.65 to 6.27 (m, 2H)

Example 22 In Example 17, (24R, 22E) -1α-methoxycarbonyloxy-25-tetrahydrofuranyloxyergosta-5,7,22-trien-3β-ol 70.2 mg (0.126 mmol) Instead of (2
4S, 22E) -1α-allyloxycarbonyloxy-25-methoxymethoxyergosta-5,7,22-
Using trien-3β-ol, and pyridinium p-
Reaction and separation and purification were performed in the same manner except that p-toluenesulfonic acid was used instead of 5 mg of toluenesulfonate to obtain the following physical properties (24S, 22
E) -1α-allyloxycarbonyloxyergosta-5,7,22-triene-3β, 25-diol 5
2.9 mg was obtained (82% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.63 (s, 3H), 0.92 to 1.08 (m, 9
H), 1.13 (s, 3H), 1.15 (s, 3H),
4.02 (brm, 1H), 4.53 to 4.66 (br
m, 2H), 4.83 (brs, 1H), 5.03-
5.54 (m, 5H), 5.65 to 6.25 (m, 2
H)

Example 23 3 ml of diisopropylamine was added to tetrahydrofuran 40
Then, 13 ml of butyllithium (1.6 M hexane solution) was added dropwise to the resulting solution at -78 ° C. A solution obtained by dissolving 1.68 g of cyclopropyl methyl ketone in 10 ml of tetrahydrofuran was added to this solution.
The mixture was added dropwise at 8 ° C and stirred for 1 hour. To this solution, 18 mmol of 1α-ethoxycarbonyloxy-3β- (t-butyldimethylsilyloxy) pregna-5,7-diene-20-carbaldehyde was added in 30 m of tetrahydrofuran.
The resulting solution was added dropwise at -78 ° C and stirred for 1 hour. An aqueous ammonium chloride solution was added to the reaction solution,
After the temperature was raised to room temperature, extraction was performed with diethyl ether, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 100 ml of chloroform and 200 ml of toluene.
Add 1.5 g of p-toluenesulfonic acid and add 20 g at 60 ° C.
Stirred for minutes. Ethyl acetate was added to the obtained reaction solution, washed with aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was treated with tetrahydrofuran (100 m).
and added a tetrahydrofuran solution of tetrabutylammonium fluoride (1M solution), followed by stirring for 30 minutes. The reaction solution is poured into water, extracted with ethyl acetate, the extract is washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain 1α-ethoxy. Carbonyloxy-20- (3-cyclopropyl-3-oxo-1-
7.55 g of (propenyl) pregna-5,7-dien-3β-ol were obtained. 1α-ethoxycarbonyloxy-
20- (3-cyclopropyl-3-oxo-1-propenyl) pregna-5,7-dien-3β-ol 4.8
To a solution consisting of 2 g (10 mmol) and 50 ml of tetrahydrofuran were added 25 ml of a 0.4 M solution of cerium trichloride hexahydrate in methanol and 15 ml of methanol, and then 1 g of sodium borohydride was added little by little under ice-cooling, followed by stirring for 10 minutes. . Dilute the resulting reaction solution with water,
The mixture was extracted with methylene chloride, and the extract was washed with brine. After drying over anhydrous sodium sulfate, the mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give 1α- (ethoxycarbonyloxy) -20- (3-cyclopropyl-3
4.60 g of -hydroxy-1-propenyl) pregna-5,7-dien-3β-ol were obtained. ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.17-0.4 (m, 4H), 0.4-0.6 (m,
1H), 0.64 (s, 3H), 0.9-1.1 (m,
6H), 1.2-2.2 (m, 17H), 2.2-2.
42 (m, 2H), 2.45-2.62 (m, 2H),
3.4-3.5 (m, 1H), 3.92-4.07
(M, 1H), 4.2 (q, 2H, J = 7 Hz) 4.8
2 (brs, 1H), 5.38 (brs, 1H), 5.
4-5.6 (m, 2H), 5.67 (brs, 1H)

Example 24 In Example 16, (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of 3-tetrahydrofuranyloxybutyl) phenylsulfone,
Using 43.6 mmol of methyl-3-triethylsilyloxybutyl) phenylsulfone and 10 g of 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde (21.7 mmol)
1) Instead of 1α-methoxycarbonyloxy-3β
By performing the reaction and separation and purification in the same manner except that 21.7 mmol of-(1-ethoxyethoxy) pregna-5,7-diene-20-carbaldehyde was used,
1α-methoxycarbonyloxy-3β- (1-ethoxyethoxy) -23-phenylsulfonyl-25- (triethylsilyloxy) cholesta-5,7-diene-2
16.1 g of 2-ol was obtained (86% yield). Then, (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-2
Instead of 5-tetrahydrofuranyloxycholesta-5,7-dien-22-ol 5.4 mmol, 1α-methoxycarbonyloxy-3β- (1-ethoxyethoxy) -23-phenylsulfonyl-25- (triethylsilyloxy) The same reaction and separation and purification were carried out except that 5.4 mmol of cholesta-5,7-dien-22-ol was used, whereby 1α-methoxycarbonyloxy-3β- (1-ethoxyethoxy) -25- (triethyl 1.17 g of silyloxy) cholesta-5,7,22-triene was obtained (33% yield). 1α-methoxycarbonyloxy-3β- (1-ethoxyethoxy)-
25- (triethylsilyloxy) cholesta-5,7,
0.66 g (1 mmol) of 22-triene was dissolved in 10 ml of methanol, 10 mg of pyridinium p-toluenesulfonate was added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1α-methoxycarbonyloxy-25- (triethylsilyloxy) cholesta-5,7,22-triene-3 having the following physical data.
0.50 g of β-ol was obtained (yield: 85%). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.50 (m, 6H), 0.64 (s, 3H), 0.9
1-1.05 (m, 15H), 1.13 (s, 3H),
1.17 (s, 3H), 3.78 (s, 3H), 4.0
0 (brs, 1H), 4.80 (brs, 1H), 5.
2-5.4 (m, 3H), 5.64-5.67 (m, 1
H)

Example 25 In Example 16, (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of 3-tetrahydrofuranyloxybutyl) phenylsulfone,
Methyl-3-tetrahydrofuranyloxypentyl) phenyl sulfone (43.6 mmol) and 1α, 3
β-bis (methoxycarbonyloxy) pregna-5
10 g of 7-diene-20-carbaldehyde (21.7
The same reaction and separation and purification were carried out except that 21.7 mmol of 1α, 3β-bis (phenoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde was used in place of 1α, 3β.
15.1 g of -bis (phenoxycarbonyloxy) -26-methyl-23-phenylsulfonyl-25- (tetrahydrofuranyloxy) cholesta-5,7-dien-22-ol was obtained (yield 79%). Then (24S)
-1α, 3β-bis (methoxycarbonyloxy) -2
4-methyl-23-phenylsulfonyl-25-tetrahydrofuranyloxycholesta-5,7-diene-22
1α, 3β-bis (phenoxycarbonyloxy) -26-methyl-23 instead of all-5.4 mmol
-Phenylsulfonyl-25- (tetrahydrofuranyloxy) cholesta-5,7-dien-22-ol5.
The reaction and separation and purification were carried out in the same manner except that 4 mmol was used, whereby 1α-phenoxycarbonyloxy26-methyl-25- (tetrahydrofuranyloxy) cholesta-5,7,22-trien-3β-ol was converted to 1 0.35 g was obtained (yield 41%). In Example 17, (24R, 22E) -1α-methoxycarbonyloxy-25-tetrahydrofuranyloxyergosta-
5,7,22-trien-3β-ol 70.2mg
(0.126 mmol) instead of 1α-phenoxycarbonyloxy-26-methyl-25- (tetrahydrofuranyloxy) cholesta-5,7,22-triene-
Reaction and separation and purification were carried out in the same manner except that 3β-ol was used to obtain the following physical properties (22E)
-26-methyl-1α- (phenoxycarbonyloxy) cholesta-5,7,22-triene-3β, 25-
64.6 g of diol was obtained (96% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.64 (s, 3H), 0.94-1.05 (m, 6
H), 4.84 (brs, 1H), 5.23-5.4.
(M, 3H), 5.63-5.67 (brm, 1H),
7.1-7.5 (m, 5H)

Example 26 3 ml of diisopropylamine was added to tetrahydrofuran 40
Then, 13 ml of butyllithium (1.6 M hexane solution) was added dropwise to the resulting solution at -78 ° C. A solution obtained by dissolving 1.72 g of isopropyl methyl ketone in 10 ml of tetrahydrofuran was added to this solution.
C. and the mixture was stirred for 1 hour. To this solution, 18 mmol of 1α-benzyloxycarbonyloxy-3β- (tetrahydrofuranyloxy) pregna-5,7-diene-20-carbaldehyde was added with 30 m of tetrahydrofuran.
The resulting solution was added dropwise at -78 ° C and stirred for 1 hour. An aqueous ammonium chloride solution was added to the reaction solution,
After the temperature was raised to room temperature, extraction was performed with diethyl ether, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 100 ml of chloroform and 200 ml of toluene.
Add 1.5 g of p-toluenesulfonic acid and add 20 g at 60 ° C.
Stirred for minutes. Ethyl acetate was added to the obtained reaction solution, washed with aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the obtained residue was dissolved in 100 ml of methylene chloride, a catalytic amount of pyridinium p-toluenesulfonate was added, and 2 ml of dihydrofuran was added.
Stirred for hours. Aqueous sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. Concentrate under reduced pressure,
The obtained residue was dissolved in ethanol (20 ml) and added dropwise to a solution of sodium borohydride (0.5 g) suspended in ethanol (20 ml). After stirring at room temperature for 30 minutes, the mixture was diluted with water and extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of methylene chloride, and 2 g of imidazole was added to this solution.
-Butyldimethylsilyl chloride (4 g) at room temperature.
Stirred for hours. The reaction solution was poured into water, extracted with ethyl acetate, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give (22E) -1α-benzyloxycarbonyloxy-24- (tert- 5.36 g of (butyldimethylsilyloxy) cholesta-5,7,22-trien-3β-ol was obtained (yield: 45%). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.05 (s, 6H), 0.63 (s, 3H), 0.8
7-1.10 (m, 21H), 4.00 (brm, 1
H), 4.37 (m, 1H), 4.83 (brs, 1
H), 5.18-5.39 (m, 5H), 5.66-
5.68 (brm, 1H), 7.26 (brs, 5H)

Example 27 In Example 16, (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of (3-tetrahydrofuranyloxybutyl) phenyl sulfone, (2
R)-(2,3-dimethylbutyl) phenylsulfone 4
The reaction and separation and purification were carried out in the same manner except that 3.6 mmol was used to obtain (24R) -1α, 3β-bis (isobutoxycarbonyloxy) -24-methyl-
23-phenylsulfonylcholesta-5,7-diene-
15.4 g of 22-ol was obtained (yield 92%). Then, in Example 16, (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23
-Phenylsulfonylcholesta-5,7-diene-22
-(24R) -1α instead of all 5.4 mmol,
3β-bis (isobutoxycarbonyloxy) -24-
Methyl-23-phenylsulfonylcholesta-5,7-
Reaction and separation and purification were carried out in the same manner except that 5.4 mmol of dien-22-ol was used to obtain (24R, 22E) -1α- (isobutoxycarbonyloxy) ergosta-5,7, having the following physical properties. 1.41 g of 22-trien-3β-ol was obtained (yield 51%). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.63 (s, 3H), 0.89-1.10 (m, 21
H), 3.99-4.15 (m, 3H), 4.82 (b
rs, 1H), 5.20-5.4 (m, 3H), 64-
5.66 (brm, 1H)

Example 28 In Example 16, 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde 21.7 mmol was used instead of 1α-methoxycarbonyloxy-3β- (tert- (2S) using 21.7 mmol of butyldimethylsilyloxy) pregna-5,7-diene-20-carbaldehyde
13.6 g (43.6 mm) of-(2,3-dimethyl-3-tetrahydrofuranyloxybutyl) phenyl sulfone
ol) instead of (4-triethylsilyloxy-4-)
Reaction and separation and purification were carried out in the same manner except that 43.6 mmol of methylpentyl) phenylsulfone was used to obtain 1α-methoxycarbonyloxy-3β- (t
tert-butyldimethylsilyloxy) -23-phenylsulfonyl-25- (triethylsilyloxy) -2
4-Homocholesta-5,7-dien-22-ol 1
7.6 g was obtained (93% yield). Then (24S) -1
α, 3β-bis (methoxycarbonyloxy) -24
Methyl-23-phenylsulfonylcholesta-5,7-
1α- instead of 5.4 mmol of dien-22-ol
Methoxycarbonyloxy-3β- (tert-butyldimethylsilyloxy) -23-phenylsulfonyl-
Reaction and separation and purification were carried out in the same manner except that 25- (triethylsilyloxy) -24-homocholesta-5,7-dien-22-ol (5.4 mmol) was used, whereby 1α-methoxycarbonyloxy-3β- ( te
rt-butyldimethylsilyloxy) -25- (triethylsilyloxy) -24-homocholesta-5,7,2
2.55 g of 2-triene was obtained (66% yield). 1α-
2.15 g of methoxycarbonyloxy-3β- (tert-butyldimethylsilyloxy) -25- (triethylsilyloxy) -24-homocholesta-5,7,22-triene was dissolved in 50 ml of tetrahydrofuran, and tetrafluorofuran was added to this solution. 10 ml of a butylammonium tetrahydrofuran solution (1 M) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1α-methoxycarbonyloxy-24-homocholester-5 having the following physical properties. , 7-Diene-3β, 25-diol 1.39
g was obtained (95% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.62 (s, 3H), 0.94 (m, 6H), 1.1
3 (s, 3H), 1.17 (s, 3H), 3.78
(S, 3H), 3.99 (brm, 1H), 4.82
(Brs, 1H), 5.20-5.40 (brm, 3
H), 5.60-5.70 (brm, 1H)

Example 29 The procedure of Example 16 was repeated except that (2S)-(2,3-dimethyl-
Instead of 13.6 g (43.6 mmol) of (3-tetrahydrofuranyloxybutyl) phenyl sulfone, (5-
Reaction and separation and purification were carried out in the same manner except that 43.6 mmol of triethylsilyloxy-5-methylpentyl) phenylsulfone was used to obtain 1α, 3β-bis (methoxycarbonyloxy) -23-phenylsulfonyl-25- ( Triethylsilyloxy) -24-dihomocholesta-5,7-dien-22-ol 16.9
g (94% yield). Then (24S) -1α, 3
β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonylcholesta-5,7-dien-22-ol Instead of 5.4 mmol, 1α, 3β-
Bis (methoxycarbonyloxy) -23-phenylsulfonyl-25- (triethylsilyloxy) -24
Dihomocholesta-5,7-dien-22-ol 5.4
The reaction and separation and purification were carried out in the same manner except that mmol was used, whereby 1α-methoxycarbonyloxy-
25- (triethylsilyloxy) -24-dihomocholesta-5,7,22-trien-3β-ol 2.03
g was obtained (yield 61%). 1.85 g of 1α-methoxycarbonyloxy-25- (triethylsilyloxy) -24-dihomocholesta-5,7,22-trien-3β-ol is dissolved in 50 ml of tetrahydrofuran, and a solution of tetrabutylammonium fluoride in tetrahydrofuran is added to this solution. (1M) 10 ml was added and stirred at 50 ° C. for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1α-methoxycarbonyloxy-24-dihomocholester-5 having the following physical properties. , 7-Diene-3β, 25-diol 1.3
1 g was obtained (87% yield). ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.61 (s, 3H), 0.96 (m, 6H), 1.1
4 (s, 3H), 1.17 (s, 3H), 3.78
(S, 3H), 4.00 (brm, 1H), 4.81
(Brs, 1H), 5.2-5.4 (brm, 3H),
5.6-5.7 (brm, 1H)

Example 30 In Example 16, 1α, 3β-bis (methoxycarbonyloxy) pregna-5,7-diene-20-carbaldehyde was replaced with 21.7 mmol of 1α-methoxycarbonyloxy-3β-hydroxypregna. −5
7-diene-20-carbaldehyde 21.7 mmol
The reaction and separation and purification were carried out in the same manner except that was used to obtain (24S) -1α-methoxycarbonyloxy-24-methyl-23-phenylsulfonyl-25-
17.6 g of (tetrahydrofuranyloxy) cholesta-5,7-diene-3β, 22-diol was obtained (yield 9).
3%). (24S) -1α, 3β-bis (methoxycarbonyloxy) -24-methyl-23-phenylsulfonyl-25- (tetrahydrofuranyloxy) cholesta-5,7-dien-22-ol Instead of 5.4 mmol of (24S) ) -1α-Methoxycarbonyloxy-2
4-methyl-23-phenylsulfonyl-25- (tetrahydrofuranyloxy) cholesta-5,7-diene-
The same physical property values as those obtained in Example 16 were obtained by performing the same reaction and separation and purification except that 5.4 mmol of 3β, 22-diol was used (24R, 22
E) -1α-Methoxycarbonyloxy-25- (tetrahydrofuranyloxy) ergosta-5,7,22-
1.38 g of trien-3β-ol was obtained (yield 46).
%).

Examples 31 to 41 The reaction mixtures obtained after irradiation with ultraviolet light were each concentrated under reduced pressure in the same manner as in Examples 4 and 6 to 15, and the residue was subjected to silica gel chromatography to give each. A 1α-alkoxycarbonyloxy previtamin D ₂ derivative having the following physical properties was obtained.

(24R, 22E) -1α-methoxycarbonyloxy-9,10-secoergosta-5 (1
0), 6,8,22-Tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.71 (s, 3H), 1.00 (d, 3H, J = 7.
0 Hz), 1.05 (d, 3H, J = 6.5 Hz),
1.13 (s, 3H), 1.17 (s, 3H), 3.7
9 (s, 3H), 4.00 (brm, 1H), 5.20
−5.41 (m, 3H), 5.51 (brm, 1H),
5.79 (d, 1H, J = 11.9 Hz), 5.88
(D, 1H, J = 11.9 Hz)

(24R, 22E) -1α-ethoxycarbonyloxy-25- (tetrahydrofuran-2-yloxy) -9,10-secoergosta-5 (10),
6,8,22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.70 (s, 3H), 0.98 (d, 3H), 1.0
2 (d, 3H), 1.13 (s, 3H), 1.18
(S, 3H), 3.77 (m, 2H), 4.00-4.
20 (m, 3H), 5.21-5.40 (m, 4H),
5.50 (brm, 3H), 5.80 (d, 1H, J =
12.0 Hz) 5.89 (d, 1H, J = 12.1H
z)

(24S, 22E) -1α-allyloxycarbonyloxy-25- (methoxymethoxy) -9,
10-secoergosta-5 (10), 6,8,22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.68 (s, 3H), 0.99 (d, 3H, J = 6.
9 Hz), 1.04 (d, 3H, J = 6.6 Hz),
1.12 (s, 3H), 1.16 (s, 3H), 3.4
0 (s, 3H), 4.05 (brm, 1H), 4.54
-4.63 (m, 3H), 5.07-5.51 (m, 6
H), 5.70-6.29 (m, 3H)

(24S, 22E) -1α-allyloxycarbonyloxy-9,10-secoergosta-5 (1
0), 6,8,22-Tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.70 (s, 3H), 0.98 (d, 3H, J = 6.
9 Hz), 1.02 (d, 3H, J = 6.5 Hz),
1.13 (s, 3H), 1.15 (s, 3H), 4.0
4 (brm, 1H), 4.53-4.62 (m, 2
H), 5.06-5.52 (m, 6H), 5.69-
6.27 (m, 3H)

20- (3-cyclopropyl-3-hydroxy-1-propenyl) -1α-ethoxycarbonyloxy-9,10-secopregna-5 (10), 6,8-
Triene-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.70 (s, 3H), 1.01 (d, 3H), 4.0
3-4.21 (m, 3H), 4.40 (m, 1H),
5.21-5.53 (m, 4H), 5.80 (d, 1
H), 5.89 (d, 1H)

(22E) -1α-methoxycarbonyloxy-25-triethylsilyloxy-9,10-secocholesta-5 (10), 6,8,22-tetraen-3
β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.51 (q, 6H), 0.70 (s, 3H), 0.9
0-1.04 (m, 12H), 1.13 (s, 3H),
1.18 (s, 3H), 3.77 (s, 3H), 4.0
6 (brm, 1H), 5.18-5.41 (m, 3
H), 5.53 (brm, 1H), 5.77 (d, 1
H), 5.88 (d, 1H)

(22E) -26-methyl-1α- (phenoxycarbonyloxy) -9,10-secocholesta
5 (10), 6,8,22-tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.73 (s, 3H), 1.03 (d, 3H), 1.1
5 (s, 3H), 4.05 (brm, 1H), 5.20
-5.42 (m, 4H), 5.50 (brm, 1H),
5.80 (d, 1H, J = 11.9 Hz), 5.89
(D, 1H, J = 11.9 Hz), 7.1-7.5
(M, 5H)

(22E) -1α-benzyloxycarbonyl-24- (tert-butyldimethylsilyloxy) -9,10-secocholesta-5 (10), 6,8,
22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.05 (s, 6H), 0.70 (s, 3H), 0.8
8 (s, 9H), 1.02 (d, 3H), 4.03 (b
rm, 1H), 4.38 (m, 1H), 5.19-5.
40 (m, 5H), 5.48 (m, 1H), 5.77
(D, 1H), 5.87 (d, 1H), 7.25 (br
s, 5H)

(24R, 22E) -1α-isobutoxycarbonyloxy-9,10-secoergosta-5 (1
0), 6,8,22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.72 (s, 3H), 0.88-1.14 (m, 18
H), 4.05-4.17 (m, 3H), 5.22-
5.50 (m, 4H), 5.77 (d, 1H, J = 1
1.8 Hz), 5.87 (d, 1H, J = 11.8H)
z)

1α-methoxycarbonyloxy-24-
Homo-9,10-secocholesta-5 (10), 6,8,
22-tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.70 (s, 3H), 1.00 (d, 3H, J = 7.
0 Hz), 1.14 (s, 3H), 3.79 (s, 3H)
H), 1.67 (s, 3H), 3.79 (s, 3H),
4.03 (brm, 1H), 5.20-5.40 (m,
3H), 5.51 (brm, 1H), 5.79 (d, 1
H, J = 12.0 Hz), 5.89 (d, 1H, J = 1)
1.9Hz)

1α-methoxycarbonyloxy-24-
Dihomo-9,10-secocholesta-5 (10), 6,
8,22-tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.70 (s, 3H), 1.00 (d, 3H, J = 6.
7 Hz), 1.14 (s, 3H), 1.18 (s, 3
H), 1.67 (brm, 1H), 3.79 (s, 3
H), 4.01 (brm, 1H), 5.21-5.40.
(M, 3H), 5.51 (brm, 1H), 5.80
(D, 1H, J = 11.9 Hz), 5.89 (d, 1
H, J = 11.9 Hz)

Examples 42 to 52 Each of the reaction mixtures obtained by heating under reflux in the same manner as in Examples 4 and 6 to 15 was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. A 1α-alkoxycarbonyloxy previtamin D ₂ derivative having the following physical properties was obtained.

(24R, 22E) -1α-methoxycarbonyloxy-9,10-secoergosta-5,7,1
0 (19), 22-tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.54 (s, 3H), 0.99 (d, 3H, J = 7.
0 Hz), 1.03 (d, 3H, J = 6.8 Hz),
1.12 (s, 3H), 1.17 (s, 3H), 3.7
6 (s, 3H), 4.20 (brm, 1H), 5.07
(Brs, 1H), 5.20-5.39 (m, 4H),
5.94 (d, 1H, J = 11.1 Hz), 6.38
(D, 1H, J = 11.3 Hz)

(24R, 22E) -1α-ethoxycarbonyloxy-25- (tetrahydrofuran-2-yloxy) -9,10-secoergosta-5,7,10
(19), 22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.98 (d, 3H), 1.0
2 (d, 3H), 1.12 (s, 3H), 1.18
(S, 3H), 3.77 (m, 2H), 4.18-4.
23 (m, 3H), 4.99 (brs, 1H), 5.2
7-5.40 (m, 5H), 5.97 (d, 1H, J =
11.1 Hz), 6.37 (d, 1H, J = 11.1H)
z)

(24S, 22E) -1α-allyloxycarbonyloxy-25- (methoxymethoxy) -9,
10-Seco Ergosta-5, 7, 10 (19), 22-
Tetraene-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.99 (d, 3H, J = 6.
9 Hz), 1.03 (d, 3H, J = 6.6 Hz),
1.12 (s, 3H), 1.15 (s, 3H), 3.4
1 (s, 3H), 4.22 (brm, 1H), 5.08
−5.46 (m, 6H), 5.70-6.30 (m, 2
H), 6.36 (d, 1H, J = 11.0 Hz)

(24S, 22E) -1α-allyloxycarbonyloxy-9,10-secoergosta-5,
7,10 (19), 22-tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.98 (d, 3H, J = 6.
8 Hz), 1.03 (d, 3H, J = 6.7 Hz),
1.13 (s, 3H), 1.15 (s, 3H), 4.2
0 (brm, 1H), 4.58-4.62 (m, 2
H), 5.01 (brs, 1H), 5.08-5.47.
(M, 6H), 5.68-6.29 (m, 2H), 6.
36 (d, 1H, J = 10.8 Hz)

20- (3-Cyclopropyl-3-hydroxy-1-propenyl) -1α-ethoxycarbonyloxy-9,10-secopregna-5,7,10 (19)
-Triene-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.96 (d, 3H), 4.1
8-4.23 (m, 3H), 4.41 (m, 1H),
5.00 (brs, 1H), 5.27-5.37 (m,
4H), 6.01 (d, 1H), 6.37 (d, 1H)

(22E) -1α-methoxycarbonyloxy-25-triethylsilyloxy-9,10-secocholesta-5,7,10 (19), 22-tetraene-
3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.50-0.55 (m, 9H), 0.90-1.04
(M, 12H), 1.15 (s, 3H), 1.18
(S, 3H), 3.77 (s, 3H), 4.21 (br
m, 1H), 5.02 (m, 1H), 5.26-5.3.
3 (m, 4H), 6.00 (d, 1H), 6.36
(D, 1H),

(22E) -26-methyl-1α- (phenoxycarbonyloxy) -9,10-secocholesta
5,7,10 (19), 22-tetraene-3β, 25
-Diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.98 (d, 3H), 1.1
7 (s, 3H), 4.22 (brm, 1H), 5.00
(Brs, 1H), 5.25-5.36 (m, 1H),
6.02 (d, 1H, J = 11.1 Hz), 6.36
(D, 1H, J = 11.1 Hz), 7.1-7.5
(M, 5H)

(22E) -1α-benzyloxycarbonyl-24- (tert-butyldimethylsilyloxy) -9,10-secocholesta-5,7,10 (1
9), 22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.06 (s, 6H), 0.56 (s, 3H), 0.8
8 (s, 9H), 0.96 (d, 3H), 4.22 (b
rm, 1H), 4.39 (m, 1H), 5.00 (br
s, 1H), 5.19-5.40 (m, 6H), 5.4.
8 (m, 1H), 6.00 (d, 1H), 6.35
(D, 1H), 7.27 (brs, 5H)

(24R, 22E) -1α-isobutoxycarbonyloxy-9,10-secoergosta-5
7,10 (19), 22-tetraen-3β-ol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 0.90-1.04 (m, 9
H), 4.08-4.23 (m, 3H), 5.01 (b
rs, 1H), 5.25-5.37 (m, 4H), 6.
00 (d, 1H, J = 11.0 Hz), 6.37 (d,
1H, J = 11.0Hz)

1α-methoxycarbonyloxy-24-
Homo-9,10-secocholesta-5,7,10 (1
9), 22-Tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.55 (s, 3H), 1.01 (d, 3H, J = 6.
5 Hz), 1.21 (s, 6H), 3.77 (s, 3
H), 4.22 (brm, 1H), 4.99-5.09.
(M, 2H), 5.20-5.41 (m, 3H), 6.
02 (d, 1H, J = 11.2 Hz), 6.32 (d,
1H, J = 11.2Hz)

1α-methoxycarbonyloxy-24-
Dihomo-9,10-secocholesta-5,7,10 (1
9), 22-Tetraene-3β, 25-diol ¹ H- NMR spectrum (90 MHz, CDCl ₃ , TM
S) 0.56 (s, 3H), 1.01 (d, 3H, J = 6.
5 Hz), 1.22 (s, 6H), 3.78 (s, 3
H), 4.23 (brm, 1H), 5.00-5.10.
(M, 2H), 5.20-5.40 (m, 3H), 6.
01 (d, 1H, J = 11.2 Hz), 6.32 (d,
1H, J = 11.2Hz)

Comparative Example 1 (24R, 22E) -1α, 3β-bis (methoxycarbonyloxy) ergosta-5,7,22-triene-
500 mg of 25-ol is diethyl ether (available from Wako Pure Chemical Industries, Ltd.) 500 for measurement of oil and fat value and peracid value.
The resulting solution was irradiated with ultraviolet light for 4 minutes using a 400 W high-pressure mercury lamp under ice cooling while passing argon gas through the resulting solution. The reaction mixture was concentrated under reduced pressure, and the obtained concentrated solution was dissolved in 100 ml of diisopropyl ether (purification by distillation in the presence of sodium-benzophenone ketyl), and the mixture was refluxed for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure.
ml and 25 ml of methanol were added, and the mixture was stirred at room temperature for 3 hours. The crystals were filtered and washed with cold methanol. The crystals were dried under reduced pressure to recover 53 mg of (24R, 22E) -1α- (methoxycarbonyloxy) ergosta-5,7,22-triene-3β, 25-diol. The filtrate and the washings were combined, neutralized with dilute hydrochloric acid under ice-cooling, added with aqueous sodium bicarbonate, and concentrated under reduced pressure. The concentrate was extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure, and purified by silica gel column chromatography. Unreacted (24R, 22E) -1α,
3β-bis (methoxycarbonyloxy) ergosta
5,7,22-trien-25-ol could not be recovered,
115 mg of a fraction containing vitamins were obtained. The vitamin-containing fraction was further purified by high performance liquid chromatography to give (24R, 22E) -9,10-secoergosta-5,7,10 (19), 22-tetraene-1α, 3.
58.0 mg of β, 25-triol were obtained [Yield: based on (24R, 22E) -1α, 3β-bis (methoxycarbonyloxy) ergosta-5,7,22-trien-25-ol consumed. 14.7%].

Comparative Example 2 (24R, 22E) -1α, 25-bis (acetoxy)
Ergosta-5,7,22-trien-3β-ol 5
00 mg was dissolved in 500 ml of diethyl ether for measurement of oil and fat value / peracid value (available from Wako Pure Chemical Industries, Ltd.),
While passing argon gas through the resulting solution, 40
Ultraviolet irradiation was performed for 4 minutes using a 0 W high-pressure mercury lamp. The reaction mixture was concentrated under reduced pressure, and the obtained concentrate was dissolved in 100 ml of diisopropyl ether (distillation and purification in the presence of sodium-benzophenone ketyl), and the solution was concentrated under a nitrogen atmosphere.
Heated to reflux for an hour. The reaction mixture was concentrated under reduced pressure, 2.5 ml of a 1 N aqueous solution of lithium hydroxide and 25 ml of methanol were added to the residue, and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with diluted hydrochloric acid under ice-cooling, aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. Concentrate under reduced pressure, purify by silica gel column chromatography, fraction containing unreacted (24R, 22E) -1α, 25-bis (acetoxy) ergosta-5,7,22-trien-3β-ol and 65 mg of vitamin 240 mg were obtained. The fraction containing vitamins was further purified by high performance liquid chromatography to give (24R, 22E) -9,
9.0 mg of 10-secoergosta-5,7,10 (19), 22-tetraene-1α, 3β, 25-triol and (24R, 22E) -25-acetoxy-9,10
-Secoergosta-5,7,10 (19), 22-tetraene-1α, 3β-diol 65.0 mg [(24R,
22E) -9,10-Seco Ergosta-5,7,10
(19), corresponding to 59.2 mg of 22-tetraene-1α, 3β, 25-triol] [Yield: consumed (24R, 22E) -1α, 25-bis (acetoxy)]
18.8% relative to ergosta-5,7,22-trien-3β-ol].

[0119]

According to the present invention, there is provided an industrially advantageous method for producing a 1α-hydroxyvitamin D ₂ derivative represented by the above general formula (I). According to the method A of the present invention, 1α-hydroxyvitamin D represented by the general formula (I) is much more efficiently and in higher yield than the above-mentioned conventional method.
_Two derivatives can be produced. In addition, according to the method B of the present invention, the compound (II) as a starting material is reused without waste, and the 1α-hydroxyvitamin D ₂ derivative represented by the general formula (I) is produced with high efficiency and high yield. can do.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-4-13692 (JP, A) WO 88/7545 (WO, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 401/00 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula (II) (Wherein, R ¹ represents an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, and A ² represents a compound represented by the general formula (b): It represents a group represented by wherein, R ² and R ³ represents a carbocyclic ring each represent a lower alkyl group or a trifluoromethyl group, or together with the carbon atoms to which they are attached, X ² And Y ² are each a hydrogen atom, a fluorine atom,
A 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the following formula (III) is represented by the following general formula (III): ## STR3 ## which represents a methyl group, a hydroxyl group or a protected hydroxyl group, and n represents an integer of 1 to 4. ] Isomer (In the formula, R ¹ and A ² is as defined above) yielding 1α- alkoxycarbonyloxy previtamin D ₂ derivative represented by, the 1α- alkoxycarbonyloxy previtamin D ₂ derivative by thermal energy By converting to the general formula (IV) (In the formula, R ¹ and A ² is as defined above) 1.alpha.-represented by alkoxycarbonyloxy vitamin D ₂
By converting the 1α-alkoxycarbonyloxyvitamin D ₂ derivative into a derivative and then removing the —OCOR ¹ group at the 1α-position and optionally a hydroxyl-protecting group from the 1α-alkoxycarbonyloxyvitamin D ₂ derivative. (Wherein A ¹ is a group represented by the general formula (a): Wherein X ¹ and Y ¹ each represent a hydrogen atom, a fluorine atom, a methyl group, a hydroxyl group or a protected hydroxyl group, and R ² , R ³ and n are as defined above. ) And an unreacted 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the above general formula (II) to form a mixture containing the 1α-hydroxyvitamin D ₂ derivative represented by the above general formula (II). _A method for producing a 1α-hydroxyvitamin D ₂ derivative represented by the above general formula (I), wherein the ₂ derivative and the 1α-alkoxycarbonyloxy provitamin D ₂ derivative are separated from each other. 2. A compound of the general formula (II) (Wherein R ¹ represents an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, and A ² represents a compound represented by the general formula (b): Represents a group represented in, wherein, R ² and R ³ represents a carbocyclic ring or represents each lower alkyl group or a trifluoromethyl group, or a carbon atom to which they are attached together, X ² And Y ² are each a hydrogen atom, a fluorine atom,
A 1-α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the following formula (III): methyl group, hydroxyl group or protected hydroxyl group, and n represents an integer of 1-4. ] Isomer (In the formula, R ¹ and A ² is as defined above) yielding 1α- alkoxycarbonyloxy previtamin D ₂ derivative represented by, the 1α- alkoxycarbonyloxy previtamin D ₂ derivative by thermal energy By conversion to the general formula (IV) (In the formula, R ¹ and A ² is as defined above) 1.alpha.-represented by alkoxycarbonyloxy vitamin D ₂
Derivatives and unreacted 1α represented by the above general formula (II)
To form a mixture containing an alkoxycarbonyloxy provitamin D ₂ derivative, and from the mixture, formula (II)
The 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the formula is separated as a crystal, which is recycled and reused, and the remaining crude compound represented by the general formula (IV) represented by the formula (IV)
The α-alkoxycarbonyloxyvitamin D ₂ derivative is freed from the 1-position —OCOR ¹ group and optionally a hydroxyl-protecting group from the D ₂ derivative to obtain a compound of the general formula (I): (Wherein A ¹ is a group represented by the general formula (a): Wherein X ¹ and Y ¹ each represent a hydrogen atom, a fluorine atom, a methyl group, a hydroxyl group or a protected hydroxyl group, and R ² , R ³ and n are as defined above. And the remaining unreacted 1α-hydroxyvitamin D ₂ derivative represented by the general formula (II)
A mixture containing an α-alkoxycarbonyloxy provitamin D ₂ derivative is produced, and the 1α-hydroxyvitamin D ₂ derivative and the 1α-alkoxycarbonyloxy provitamin D ₂ derivative are separated from the mixture to obtain a compound of the general formula (II) A method for producing a 1α-hydroxyvitamin D ₂ derivative represented by the above general formula (I), wherein the 1α-alkoxycarbonyloxy provitamin D ₂ derivative represented by the following formula (I) is recycled. 3. A compound of the general formula (II) (Wherein R ¹ and A ² are as defined in claim 1). 4. A compound of the general formula (III) (Wherein R ¹ and A ² are as defined in claim 1). 5. A compound of the general formula (IV) (Wherein R ¹ and A ² are as defined in claim 1).